The vitamin D prodrugs 1α(OH)D2 1α(OH)3 and BCI-210 suppress PTH secretion by bovine parathyroid cells

Abstract

Background. Active vitamin D compounds are widely used in the treatment of secondary hyperparathyroidism associated with renal failure. These compounds reduce PTH secretion through vitamin D receptor (VDR)-dependent repression of PTH gene transcription. In previous studies, 1α(OH)D3, a vitamin D prodrug, inhibited PTH secretion in cultured bovine parathyroid cells, but it was unclear whether 1α(OH)D3 itself or an active metabolite produced this inhibition. Methods. We determined the effectiveness of the vitamin D prodrugs 1α(OH)D3, 1α(OH)D2 and 1α(OH)-24(R)-methyl-25-ene-D2 (BCI-210) at inhibiting PTH secretion in bovine parathyroid cell cultures, and examined the metabolism of [3H]1α(OH)D2 in these cells. Results. All three prodrugs suppressed PTH secretion with approximately 10% of the activity of 1,25(OH)2D3; much higher activity than expected based on the VDR affinities of these prodrugs (0.25% of 1,25(OH)2D3). Parathyroid cells activated [3H]1α(OH)D2 to both 1,25(OH)2D2 and 1,24(OH)2D2 1,24(OH)2D2 was detectable at 4h, increased to a maximum at 8h, and then decreased. In contrast, 1,25(OH)2D2 levels increased linearly with time, suggesting the presence of constitutively active vitamin D-25-hydroxylase not previously reported in parathyroid cells. The cytochrome P-450 inhibitor ketoconazole (50p;μM) reduced 1α(OH)D2 metabolism to below detectable levels, but did not significantly affect suppression of PTH by 1α(OH)D2. Conclusions. The vitamin D prodrugs 1α(OH)D3, 1α(OH)D2 and BCI-210 suppressed PTH production by cultured parathyroid cells. The ability of 1α(OH)D2 to reduce PTH despite inhibition of its metabolism suggests a direct action of this 'prodrug' on the parathyroid gland, but the mechanism underlying this activity is not yet known. © 2005 Oxford University Press.